Major depressive disorder (MDD) during pregnancy and postpartum depression are associated with significant maternal and neonatal morbidity. While antidepressants are readily used in pregnancy, studies have raised concerns regarding neurobehavioral outcomes in exposed infants. Omega-3 fatty acid supplementation, most frequently from fish oil, has emerged as a possible treatment or prevention strategy for MDD in non-pregnant individuals, and may have beneficial effects in pregnant women. Although published observational studies in the psychiatric literature suggest that maternal DHA deficiency may lead to the development of MDD in pregnancy and postpartum, there are more intervention trials suggesting clinical benefit for supplementation with EPA-rich fish oil in MDD. The objective of the proposed research is to compare the efficacy of EPA-rich fish oil with DHA-rich fish oil supplementation in the prevention of MDD in pregnant women at risk for depression. The proposed study is a randomized placebo controlled trial that will identify 125 women early in pregnancy to measure longitudinally: i) depressive symptoms;ii) proinflammatory cytokines IL-6, IL-1? and TNF-?;and iii) plasma levels of EPA and DHA, up to 6 weeks postpartum. It is hypothesized that EPA-rich fish oil and DHA-rich fish oil supplementation will reduce the risk of antenatal and postpartum depression in women at elevated risk (previous history of MDD, previous history of postpartum depression, or a Edinburgh Postnatal Depression Scale score between 10 and 19 at baseline). Participants will be randomly assigned to take one of three interventions medications daily: i) 2 EPA- rich fish oil capsules ii) 2 DHA-rich fish oil capsules;or iii) 2 placebo capsules. The goal of the proposed study is to generate preliminary data on the feasibility, optimal preparation (EPA-rich versus DHA-rich), effect size, and possible mechanism of action of fish oil for the prevention of depressive symptoms in pregnancy and postpartum, which will inform a larger multi-center randomized controlled trial in the future. The proposed study is responsive to the NCCAM Strategic Plan for 2005-2009, which calls for research on both the effects of CAM practices on the health of the fetus and mother during pregnancy and on enhancing physical and mental health and wellness. PUBLIC HEALTH RELEVANCE: Major depressive disorder is a significant cause of maternal morbidity during and subsequent to pregnancy. The objective of this project is to compare the efficacy of EPA-rich fish oil and DHA-rich fish oil in reducing the incidence and severity of depressive symptoms during pregnancy and postpartum. This proposal is designed to generate important data and hypotheses for the design and execution of future studies on the effects of fatty acids on mood disorders in pregnancy and postpartum and on infant and child development.